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Wednesday, August 20, 2025

Antianginal agents


Introduction

Angina pectoris is a clinical syndrome characterized by chest discomfort resulting from myocardial ischemia, usually due to coronary artery disease (CAD). It arises when the oxygen demand of the heart exceeds its oxygen supply, often because of narrowed coronary arteries.

Antianginal agents are drugs used to prevent or treat anginal attacks by either:

  • Reducing myocardial oxygen demand (by lowering heart rate, contractility, or afterload), or

  • Increasing oxygen supply (by dilating coronary arteries or improving perfusion).

These agents do not cure the underlying atherosclerotic disease but improve quality of life, exercise tolerance, and reduce anginal episodes. Some (such as beta-blockers and certain calcium channel blockers) also reduce mortality in patients with ischemic heart disease.


Pathophysiological Basis of Angina

  1. Stable Angina (Effort Angina)

    • Caused by fixed coronary artery narrowing.

    • Triggered by exertion, stress, or large meals.

    • Relieved by rest or nitrates.

  2. Unstable Angina

    • Due to plaque rupture, thrombus formation, or dynamic vasoconstriction.

    • Higher risk of myocardial infarction (part of acute coronary syndrome).

  3. Variant (Prinzmetal’s) Angina

    • Caused by coronary artery spasm, even without fixed obstruction.

    • Occurs at rest, often at night.

Antianginal drugs are chosen depending on the type and severity of angina.

Classification of Antianginal Agents

  1. Organic Nitrates

    • Nitroglycerin, Isosorbide dinitrate, Isosorbide mononitrate.

  2. Beta-Adrenergic Blockers

    • Propranolol, Atenolol, Metoprolol, Bisoprolol, Carvedilol.

  3. Calcium Channel Blockers (CCBs)

    • Dihydropyridines: Amlodipine, Nifedipine.

    • Non-dihydropyridines: Verapamil, Diltiazem.

  4. Potassium Channel Openers

    • Nicorandil.

  5. Late Sodium Current Inhibitors

    • Ranolazine.

  6. Other Adjuncts

    • Ivabradine (If channel inhibitor in SA node).

    • Trimetazidine (metabolic modulator).

Mechanisms of Action

  • Organic Nitrates: Release nitric oxide (NO) → activate guanylyl cyclase → ↑ cGMP → smooth muscle relaxation → venodilation (↓ preload), arteriolar dilation (↓ afterload), coronary dilation (↑ oxygen supply).

  • Beta-Blockers: Block β1-receptors → ↓ heart rate, ↓ contractility, ↓ myocardial oxygen demand.

  • Calcium Channel Blockers:

    • Dihydropyridines (Amlodipine): arterial vasodilation → ↓ afterload.

    • Non-DHPs (Verapamil, Diltiazem): ↓ heart rate and contractility, plus coronary vasodilation.

  • Nicorandil: Opens K+ ATP channels → hyperpolarization → vasodilation; also donates NO.

  • Ranolazine: Inhibits late sodium current (INa), reduces calcium overload → improves myocardial relaxation, lowers oxygen demand.

  • Ivabradine: Selective sinus node If current inhibitor → slows heart rate without affecting contractility.

  • Trimetazidine: Shifts myocardial metabolism from fatty acid oxidation to glucose utilization → more efficient ATP generation per oxygen molecule.

Major Antianginal Agents, Generic Names, and Doses

1. Organic Nitrates

  • Nitroglycerin (Glyceryl trinitrate, GTN)

    • Sublingual: 0.3–0.6 mg every 5 minutes as needed (max 3 doses in 15 min).

    • Transdermal patch: 0.2–0.8 mg/hr applied once daily (remove for 8–12 hrs to avoid tolerance).

    • IV infusion: 5 mcg/min, titrate upward.

  • Isosorbide Dinitrate

    • Oral: 10–40 mg every 6–8 hours.

    • Sublingual: 2.5–10 mg for acute relief.

  • Isosorbide Mononitrate

    • Oral: 20 mg twice daily (IR), or 30–60 mg once daily (SR).

2. Beta-Blockers

  • Propranolol: 40–160 mg/day PO in divided doses.

  • Metoprolol: 50–200 mg/day PO, extended-release 100 mg once daily.

  • Atenolol: 25–100 mg/day PO.

  • Bisoprolol: 5–10 mg once daily.

  • Carvedilol: 12.5–50 mg/day in divided doses.

3. Calcium Channel Blockers

  • Amlodipine (DHP): 5–10 mg PO once daily.

  • Nifedipine ER (DHP): 30–90 mg PO once daily.

  • Verapamil (Non-DHP): 120–240 mg/day in divided doses, ER 240 mg once daily.

  • Diltiazem (Non-DHP): 120–360 mg/day in divided doses or ER once daily.

4. Potassium Channel Opener

  • Nicorandil: 5–20 mg PO twice daily.

5. Late Sodium Current Inhibitor

  • Ranolazine: 500 mg PO twice daily, may increase to 1000 mg twice daily.

6. Other Agents

  • Ivabradine: 5–7.5 mg PO twice daily (adjust based on heart rate).

  • Trimetazidine: 35 mg PO twice daily (modified release).

Clinical Uses

  • Stable Angina:

    • First-line: Beta-blockers or Calcium channel blockers.

    • Add-on: Nitrates, Ranolazine, Nicorandil, Ivabradine.

  • Variant (Prinzmetal’s) Angina:

    • Best: Calcium channel blockers and nitrates.

    • Avoid beta-blockers (can worsen spasm).

  • Unstable Angina (part of ACS):

    • Nitrates for pain relief.

    • Beta-blockers for rate control and ↓ O2 demand.

    • Antiplatelet + anticoagulant therapy (not antianginal but essential).

Adverse Effects

Organic Nitrates

  • Headache (from vasodilation).

  • Flushing.

  • Hypotension, dizziness.

  • Reflex tachycardia.

  • Tolerance with continuous use.

Beta-Blockers

  • Bradycardia, AV block.

  • Bronchospasm (non-selective agents).

  • Fatigue, depression, sexual dysfunction.

  • Rebound angina on sudden withdrawal.

Calcium Channel Blockers

  • DHPs: Headache, ankle edema, flushing, reflex tachycardia.

  • Non-DHPs: Bradycardia, AV block, constipation (verapamil).

Nicorandil

  • Headache, hypotension, ulcerations (rare).

Ranolazine

  • QT prolongation.

  • Constipation, dizziness.

Ivabradine

  • Bradycardia.

  • Visual phenomena (phosphenes).

Trimetazidine

  • Parkinsonian symptoms (rare, reversible).

Contraindications

  • Nitrates: Hypotension, concurrent PDE-5 inhibitor use (sildenafil, tadalafil).

  • Beta-blockers: Severe bradycardia, AV block, asthma, decompensated heart failure.

  • Calcium channel blockers:

    • Non-DHP: Avoid in severe heart failure, AV block.

    • DHP: Avoid in severe hypotension.

  • Ranolazine: Hepatic cirrhosis, strong CYP3A inhibitors.

  • Ivabradine: Bradycardia, sick sinus syndrome.

Precautions

  • Monitor BP and HR regularly.

  • Avoid abrupt withdrawal of beta-blockers.

  • Educate patients on nitrate tolerance (nitrate-free interval).

  • ECG monitoring for QT prolongation with ranolazine.

  • Caution with polypharmacy in elderly patients.

Drug Interactions

  • Nitrates + PDE-5 inhibitors (sildenafil, tadalafil): Severe hypotension.

  • Beta-blockers + Verapamil/Diltiazem: Excessive bradycardia/AV block.

  • Ranolazine + CYP3A4 inhibitors (ketoconazole, clarithromycin): Increased drug levels, QT prolongation.

  • Ivabradine + strong CYP3A4 inhibitors (diltiazem, verapamil, macrolides): Increased toxicity risk.

Clinical Efficacy

  • Nitrates: Rapid relief of acute angina, excellent for symptomatic control.

  • Beta-blockers: Proven to reduce mortality post-MI and in stable CAD.

  • Calcium channel blockers: Effective in variant angina; alternative to beta-blockers.

  • Ranolazine, Ivabradine, Trimetazidine, Nicorandil: Valuable adjuncts in refractory angina.

  • Combination therapy is often necessary for optimal symptom control and quality of life.




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